title: Neurite outgrowth mediated by translation elongation factor eEF1A1: a target for antiplatelet agent cilostazol.
abstract: Cilostazol, a type-3 phosphodiesterase (PDE3) inhibitor, has become widely used as an antiplatelet drug worldwide. A recent second Cilostazol Stroke Prevention Study demonstrated that cilostazol is superior to aspirin for prevention of stroke after an ischemic stroke. However, its precise mechanisms of action remain to be determined. Here, we report that cilostazol, but not the PDE3 inhibitors cilostamide and milrinone, significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Furthermore, specific inhibitors for the endoplasmic reticulum protein inositol 1,4,5-triphosphate (IP(3)) receptors and several common signaling pathways (PLC-γ, PI3K, Akt, p38 MAPK, and c-Jun N-terminal kinase (JNK), and the Ras/Raf/ERK/MAPK) significantly blocked the potentiation of NGF-induced neurite outgrowth by cilostazol. Using a proteomics analysis, we identified that levels of eukaryotic translation elongation factor eEF1A1 protein were significantly increased by treatment with cilostazol, but not cilostamide, in PC12 cells. Moreover, the potentiating effects of cilostazol on NGF-induced neurite outgrowth were significantly antagonized by treatment with eEF1A1 RNAi, but not the negative control of eEF1A1. These findings suggest that eEF1A1 and several common cellular signaling pathways might play a role in the mechanism of cilostazol-induced neurite outgrowth. Therefore, agents that can increase the eEF1A1 protein may have therapeutic relevance in diverse conditions with altered neurite outgrowth.
authors.affiliation: Division of Clinical Neuroscience, Center for Forensic Mental Health, Chiba University, Chiba, Japan. hashimoto@faculty.chiba-u.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Tamaki
authors.initials: T
authors.lastname: Ishima
mesh_terms: D000818:Animals; D000077407:Cilostazol; D004357:Drug Synergism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020105:Milrinone / Q000737:chemistry / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism*; D016716:PC12 Cells; D020648:Peptide Elongation Factor 1 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051966:Phospholipase C gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology*; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000077407:Cilostazol; D053496:Inositol 1,4,5-Trisphosphate Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D020105:Milrinone; D020929:Mitogen-Activated Protein Kinase Kinases; D020932:Nerve Growth Factor; D020648:Peptide Elongation Factor 1; D019869:Phosphatidylinositol 3-Kinases; D058987:Phosphodiesterase 3 Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051966:Phospholipase C gamma; D010975:Platelet Aggregation Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D015363:Quinolones; D020917:Receptor, trkA; D013777:Tetrazoles; D048490:raf Kinases; D018631:ras Proteins; C021294:cilostamide